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Research Paper|Volume 1, Issue 4|pp 402—411

MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8

Dipa Bhaumik1, Gary K. Scott1, Shiruyeh Schokrpur1,3, Christopher K. Patil1,2, Arturo V. Orjalo1, Francis Rodier1,2, Gordon J. Lithgow1, Judith Campisi1,2
  • 1Buck Institute for Age Research, Novato, CA 94945, USA
  • 2Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
  • 3Present Address: University of California at Los Angeles, Los Angeles CA 90095, USA
Received: March 31, 2009Accepted: April 18, 2009Published: April 21, 2009
https://doi.org/10.18632/aging.100042

Copyright: © 2009 Bhaumik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Senescence is a cellular program that irreversibly arrests the proliferation of damaged cells and induces the secretion of the inflammatory mediators IL- 6 and IL-8 which are part of a larger senescence associated secretory phenotype (SASP). We screened quiescent and senescent human fibroblasts for differentially expressed microRNAS (miRNAs) and found that miRNAs 146a and 146b (miR-146a/b) were significantly elevated during senescence. We suggest that delayed miR-146a/b induction might be a compensatory response to restrain inflammation. Indeed, ectopic expression of miR-146a/b in primary human fibroblasts suppressed IL-6 and IL-8 secretion and downregulated IRAK1, a crucial component of the IL-1 receptor signal transduction pathway. Cells undergoing senescence without induction of a robust SASP did not express miR-146a/b. Further, IL-1α neutralizing antibodies abolished both miR-146a/b expression and IL-6 secretion. Our findings expand the biological contexts in which miRNA-146a/b modulates inflammatory responses. They suggest that IL-1 receptor signaling initiates both miR-146a/b upregulation and cytokine secretion, and that miR-146a/b is expressed in response to rising inflammatory cytokine levels as part of a negative feedback loop that restrains excessive SASP activity.